The proposed research involves investigations of the genetic regulation of aflatoxin B1 (AFB1) metabolism via activation and deactivation pathways; and the role of the genetics of AFB1 metabolism in mutagenesis and carcinogenesis. Compounds to be studied include AFB1 and inducers that cause induction or repression of the specific pathways of AFB1 metabolism. The objectives of these studies are: (a) to understand the genetic regulation of AFB1 metabolism via various pathways, including activation and detoxification; (b) develop genetic models for studies on aflatoxin carcinogenesis and toxicity; and (c) define the role of the genetic regulation of AFB1 metabolism, via various pathways, in the determination of susceptibility to aflatoxin B1. Much of the proposed work will include: (a) in vitro studies using labeled AFB1, DNA, hepatic microsomes and other subcellular fractions isolated from rats and mice; (b) isolation and purification of various forms of cytochrome P-450 from mice and rats for the purpose of identifying specific cytochromes involved in the detoxification and the activation of aflatoxin B1 to DNA-binding and mutagenic metabolites; and (c) comparison of the effects of smoking on the metabolism of aflatoxin B1 via various pathways, using placental tissue from maternal smokers and non-smokers. Particular methods to be used include: radiochemical techniques, thin layer chromatography, spectroscopy, ultracentrifugation techniques, HPLC and other biochemical and enzymological methods.